Abstract

Psoriasis is an immune-mediated highly heterogeneous skin disease in which genetic as well as environmental factors play important roles. In spite of the local manifestations of the disease, psoriasis may progress to affect organs deeper than the skin. These effects are documented by epidemiological studies, but they are not yet mechanistically understood. In order to provide insight into the systemic effects of psoriasis, we performed a nontargeted high-resolution LC-MS metabolomics analysis to measure plasma metabolites from individuals with mild or severe psoriasis as well as healthy controls. Additionally, the effects of the anti-TNFα drug Etanercept on metabolic profiles were investigated in patients with severe psoriasis. Our analyses identified significant psoriasis-associated perturbations in three metabolic pathways: (1) arginine and proline, (2) glycine, serine and threonine, and (3) alanine, aspartate, and glutamate. Etanercept treatment reversed the majority of psoriasis-associated trends in circulating metabolites, shifting the metabolic phenotypes of severe psoriasis toward that of healthy controls. Circulating metabolite levels pre- and post-Etanercept treatment correlated with psoriasis area and severity index (PASI) clinical scoring (R(2) = 0.80; p < 0.0001). Although the responsible mechanism(s) are unclear, these results suggest that psoriasis severity-associated metabolic perturbations may stem from increased demand for collagen synthesis and keratinocyte hyperproliferation or potentially the incidence of cachexia. Data suggest that levels of circulating amino acids are useful for monitoring both the severity of disease as well as therapeutic response to anti-TNFα treatment.

Dependency network displaying plasma metabolite relationships in psoriasis in the context of the noted metabolic perturbations between (A) severe untreated psoriasis and control, (B) severe treated and severe untreated psoriasis, and (C) severe treated psoriasis and control patients. Metabolites are connected based on partial correlation defined relationships, and edge color and width display the direction and magnitude of the FDR-adjusted Spearman rank order coefficient of correlation (padj ≤ 0.05). Vertices represent metabolites, with the shape and color displaying relative direction and statistical significance (padj ≤ 0.05) of the metabolic change for each respective comparison (i.e., panel A displays changes in severe psoriasis patients relative to controls). Metabolites are sized according to each comparison’s respective OPLS-DA model VIP (Figure ), and species in common in the exploratory and validation models’ selected feature sets are highlighted with thick black borders.